Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

• This invention relates to certain arylpiperazinoalkanol esters and their addition salts with pharmaceutically acceptable inorganic and organic acids, to pharmaceutical compositions containing them and to a method of treating mammals using them.
• the present invention provides compounds of general formula (I): ##SPC2##
• R 1 is an alkyl of 1 to 10 carbon atoms; a phenyl which is unsubstituted or substituted by one to three substituents, which may be the same or different and which is a halogen, a hydroxy, acetoxy, amino or alkoxy of 1 to 5 carbon atoms, ##SPC3##
• R 3 is a hydrogen or halogen, or a trifluoromethyl, trifluoromethoxy or trifluoromethylthio; or ##SPC4##
• R 5 is a hydrogen or halogen or R 5 is ##SPC5##
• p is an integer of 0 to 2 and each R 6 , which may be the same or different, is a halogen, an alkyl of 1 to 3 carbon atoms or a trifluoromethyl, trifluoromethoxy or trifluoromethylthio; and
• R 2 is a hydrogen or halogen, an alkoxy of 1 to 3 carbon atoms or a trifluoromethyl, trifluoromethoxy or trifluoromethylthio; or an acid addition salt thereof with a pharmaceutically acceptable organic or inorganic acid.
• the compounds of the invention are suitable for use as pharmaceuticals for use in human and veterinary therapy, especially as analgesic agents.
• R 2 and n are as defined above under conditions which are those most favourable for the acid derivative chosen.
• an acid halide, and particularly a chloride, and a compound of general formula (II) are reacted at the reflux temperature of an apolar solvent such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene; or chloroform; in this case, the presence of a tertiary base which accepts the hydrogen halide acid can be advantageous;
• an apolar solvent such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene; or chloroform
• AN ACID ANHYDRIDE AND A COMPOUND OF GENERAL FORMULA (II) are heated at 80° to 150°C; in this case, the presence of a solvent is not absolutely necessary;
• An ester, R 1 --COOR 9 wherein R 9 represents a lower alkyl group, such as methyl, ethyl or propyl, and a compound of general formula (II) are reacted at the reflux temperature of an apolar solvent such as an aromatic hydrocarbon.
• a transesterification reaction which is often promoted by the presence of an alkali metal, for example sodium, takes place.
• the reaction is preferably carried out at the reflux temperature of an apolar solvent, especially an aromatic hydrocarbon like benzene, toluene or xylene. This process is illustrated by Examples 13 to 15 below.
• the condensation step is carried out in an apolar solvent such as chloroform, working firstly under cold conditions (-20° to +20°) and then heating gradually to 50°-80° in order to complete the reaction.
• apolar solvent such as chloroform
• the subsequent reduction step is carried out catalytically or chemically, and especially by hydrogenation in the presence of palladium on charcoal. This process is illustrated by Example 18 below.
• the present invention also provides a process for preparing a compound of general formula ##SPC13##
• n, R 1 , R 2 and R 6 have the meanings given in the definition of the compounds of the general formula (I).
• the invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising, as the active ingredient, a compound of general formula (I), and a pharmaceutically acceptable carrier or diluent.
• the compositions can be those suitable for administration, orally, endorectally or parenterally.
• any pharmaceutical form suited to this method can be used; examples are tablets, dragees, gelatin-coated pills, capsules, cachets, solutions or potable suspensions.
• the unit dose of the compound can vary between 10 and 500 mg, and the daily dose between 50 and 2,000 mg.
• suppositories containing 20 to 500 mg. of the compound are used and are administered to the patient at the rate of one to four per 24 hours.
• injectable solutions for parenteral administration, injectable solutions, buffered to the physiological pH and prepared in advance or at the time of use, are employed.
• the unit dose is between 10 and 500 mg. and the maximum daily dose is 1,000 mg.
• the monohydrochloride is prepared by dissolving 9.55 g (0.0274 mol) of the above base in 70 ml of 2-propanol and adding 6.85 ml of N-hydrogen chloride in ethanol. The salt formed is filtered off and dried in vacuo to give 8.5 g (yield: 80.4%) of 2-(4-m-trifluoromethylthiophenyl-piperazino)-ethyl acetate monohydrochloride, which melts at 114°C.
• reaction mixture is filtered while hot to remove a little insoluble matter, the toluene is evaporated from the filtrate, the gummy residue is triturated in petroleum ether to convert it to a fine powder, and the powder is filtered off, dried in vacuo and recrystallised from isopropyl alcohol to give 17.2 g. (yield: 84%) of 2-(4-m-trifluoromethylphenyl-piperazino)-ethyl benzoate, which melts at 95°C.
• Example 4 The procedure of Example 4 is followed, but 5.4 g. (0.02 mol) of 2-(4-m-trifluoromethylphenylpiperazino)-ethanol, 4.5 g. (0.02 mol) of methyl 3,4,5-trimethoxybenzoate, 80 ml. of toluene and 0.02 g. of sodium are used. Reaction is complete after 8 hours of heating and slow distillation. The toluene is evaporated, the oily residue is dissolved in ether, the ethereal solution is washed with water and dried over magnesum sulphate, and the ether is driven off to give 9.2 g. (yield: 97.8%) of 2-(4-m-trifluoromethyl-phenylpiperazino)-ethyl 3,4,5-trimethoxy-benzoate as an oil.
• the amino-ester obtained is purified by chromatography on a silica column, eluting with methylene chloride/acetone (90:10). The fractions containing the pure product are combined, the solvents are driven off, and the residue is crystallised from 2-propanol to give 2.5 g. (yield: 48%) of 2-(4-m-trifluoromethylphenylpiperazino)-ethyl 2-(3-chloro-2-methylanilino)-nicotinate, which melts at 91°C.
• Analysis: C 26 H 26 ClF 3 N 4 O 2 ; molecular weight 518.971 Calculated: C, 60.17; H, 5.05; N, 10.79%. Found: C, 59.94, 60.00; H, 5.10, 5.04; N, 10.60, 10.64%.
• the hydrochloride is prepared by dissolving 10 g. (0.02 mol) of the above amino-ester in 60 ml. of methylene chloride, and 5 ml. of 4 N-hydrogen chloride in ethanol are added. The solvents are evaporated and the salt is recrystallised from ethanol to give 9.65 g. (yield: 90%) of 2-(4-p-methoxyphenylpiperazino)-ethyl 2-(m-trifluoromethylanilino)-benzoate monohydrochloride, which melts at 182°C.
• the compounds of the invention were subjected to pharmacological tests which demonstrated their valuable propertis, especially as analgesic agens.
• Table II gives the results obtained with the representative compounds, SLB 093, SLB 108, SLB 169 and SLB 198, and with amidopyrine chosen as the reference substance.
• the analgesic effect was investigated in accordance with two conventional experimental procedures.
• the compounds of the invention can thus be used in human and veterinary medicine, in the treatment of various pain syndromes.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (4)

Publications (1)

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Cited By (6)

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Citations (3)

• 1974
  • 1974-05-06 GB GB1987374A patent/GB1437868A/en not_active Expired
  • 1974-05-06 US US05/467,595 patent/US3953449A/en not_active Expired - Lifetime
  • 1974-05-09 ES ES426135A patent/ES426135A1/es not_active Expired
  • 1974-05-09 NL NL7406258A patent/NL7406258A/xx not_active Application Discontinuation

Patent Citations (3)

Non-Patent Citations (1)

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